We wish to characterize the mechanisms for responsible for focal segmental glomerulosclerosis (FSGS) and use these findings to devise more effective therapy. We have been particularly interested in FSGS associated with HIV-1 infection, and wish to determine if any cases of idiopathic FSGS are due to other viruses. Finally, we are investigating why African-Americans are at increased risk of developing FSGS, including HIV-associated, heroin-associated, and idiopathic FSGS. We hypothesize that HIV accessory proteins (Vpr, Vpu, and Vif) mediate renal injury, leading to the histologic pattern of FSGS. To test this hypothesis, we generated transgenic mice with either local renal expression (the endothelin promoter driving expression of Vpr or Vpu) or systemic, inducible expression (a chimeric tetracycline-responsive activator and a tetracycline-responsive promoter driving either Vpr or Vpu). In addition, we have examined the effects of Vpr on gene transcription using transient transfection assays in renal cells. We are currently characterizing the Vpr and Vpu transgenic mice. We have examined the possible mechanisms by which Vpr might exert a toxic effect on host cells. Following up on observations that Vpr interacts with the glucocorticoid receptor (GR), we have demonstrated that Vpr can either potentiate or suppress dexamethasone-dependent GR-mediated gene transcription depending upon the cell type. In this respect, Vpr resembles host proteins known as co-activators and co-repressors. Recently it has been noted that several of these GR-regulators have the LXXLL motif, and we found that Vpr bears two copies of this motif. When either motif is mutated, the co-activator activity is abolished. We interpret these findings to suggest that Vpr regulates gene transcription by serving as a bridge between the GR and members of the transcription complex, and that the LXXLL motif plays a critical role in this bridging function. We have prepared immortalized B cell lines as a source of DNA from approximately 80 African-American patients with FSGS, with the help of collaborators from eight medical centers around the country. We expect to initiate genetic screening within the next year, using two complementary approaches: 1) positional cloning, using polymorphic markers which are divergent between Caucasian and African populations, and 2) screening of candidate genes.